PROJECT SUMMARY Although a common theme across adult onset neurodegenerative diseases, the pathogenic role of aggregated proteins is a continuous topic of debate. For the incurable familial neurodegenerative disorder Huntington's disease (HD), resolving the accumulation of mutant huntingtin (Htt) (neuronal or cytoplasmic) is highly correlated with favorable therapeutic outcomes. Whether targeting aggregate clearance per se is beneficial, however, has remained unclear. We have previously identified a pathway by which aggregated proteins are selectively eliminated by the lysosome-mediated pathway macroautophagy. We found that the protein Alfy is central for the selective turnover of aggregates in cell based systems. During the previous funding period, we used a mouse genetics and cell biology to determine that Alfy is indeed essential turnover of aggregated proteins in adult brain, and diminishing Alfy levels in vivo modifies disease onset. In this renewal application, we will use genetic and molecular based approaches to determine if augmenting Alfy levels promotes the elimination of aggregated nuclear and cytoplasmic proteins, the mechanism by which a genetic variant of Alfy might delay the age of onset of MD, and the molecular mechanism by which Alfy permits aggregate clearance. .